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TitleStructure-guided design of picomolar-level macrocyclic TRPC5 channel inhibitors with antidepressant activity.
Journal, issue, pagesActa Pharm Sin B, Vol. 16, Issue 1, Page 371-386, Year 2026
Publish dateOct 27, 2025
AuthorsTong Che / Yixiang Chen / Xinyu Cheng / Han Hu / Xiaoyun Wu / Yuting Zhang / Xiaoqiang Yang / Yinzhen Liu / Hui Liu / Weiwei Nan / Shuangyan Wan / Mingxing Yang / Bo Zeng / Jian Li / Jin Zhang / Bing Xiong /
PubMed AbstractRecent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets-often large and flat-remain a major hurdle for developing selective ...Recent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets-often large and flat-remain a major hurdle for developing selective small molecules. TRPC5, a brain-enriched channel regulating depression and anxiety, is a promising therapeutic target, but current preclinical candidates suffer from moderate off-target effects. To address this, we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization, overcoming lipid-binding site challenges. Among these, JDIC-127 exhibited unprecedented potency with IC of 374 pmol/L-200-fold more potent than HC-070-and exceptional selectivity. Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5, minimizing activity against related TRPC channels and other ion channels. This selective inhibition aligns with preclinical evidence supporting JDIC-127's potential in treating neuropsychiatric disorders. The study demonstrates how macrocycles stabilize ligand conformations, enhance affinity, and achieve selectivity in lipid-dominated binding sites. It also highlights the synergy between macrocyclic design, cryo-EM, and computational modeling to address longstanding obstacles in ion channel drug discovery. JDIC-127 serves as a proof-of-concept for the application of macrocyclization in ion channel pharmacology, offering a roadmap for developing innovative therapeutics targeting TRP channels and beyond, with implications for a wide range of diseases.
External linksActa Pharm Sin B / PubMed:41584354 / PubMed Central
MethodsEM (single particle)
Resolution3.09 - 3.23 Å
Structure data

62784

9l3f

EMDB-62784, PDB-9l3f:
Structure-Guided Design of Picomolar-level Macrocyclic TRPC5 Channel Inhibitors with Antidepressant Activity
Method: EM (single particle) / Resolution: 3.09 Å

64801

9v6j

EMDB-64801, PDB-9v6j:
Structure-Guided Design of Picomolar-level Macrocyclic TRPC5 Channel Inhibitors with Antidepressant Activity
Method: EM (single particle) / Resolution: 3.23 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-CA:
Unknown entry

PDB-1eh7:
METHYLATED HUMAN O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE

Source
  • Homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / Ion channel / TRPC5 / Inhibitor

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